The fragile X syndrome is the most common familial cause of mental retardation known. Although males are most significantly affected, females are also affected and there is a broad range of variability in the physical, neurocognitive and emotional phenotype. Some of the factors which affect this variation in penetrance for the heterozygote include her position in the pedigree, percent fragility and X-inactivation. The overall goals of the proposed research are to better define the physical, neurocognitive and emotional/social phenotype of the fragile X heterozygote, to examine the relationships among these phenotype domains and to test different genetic and environmental explanations for the range of phenotypic expression. One promising genetic hypothesis is Laird's (1987) imprinting theory which makes specific, but as yet untested predictions about phenotypic expression in imprinted vs. nonimprinted heterozygotes. To accomplish these goals, we will study three groups of fragile X heterozygotes between the ages of 16 to 45 and with an IQ of 65 or higher: 1) those who do not express the fragile X chromosome but are obligate carriers or DNA probe positive for the gene (nonimprinted), 2) those who express the fragile X gene in >2 but <10% of their cells (mixed imprinted and nonimprinted, and 3) those who express the fragile X chromosome in >10% of their cells (imprinted females). To evaluate environmental sources of phenotype variance, we will utilize nonfragile X control females who have experienced the stressor of either up in a fragile X family or raising a developmentally delayed child. An extensive evaluation in three domains will occur: 1) In the physical/historical domain, a history of medical, school and behavioral problems will be obtained. A physical exam will also document features which are associated with the fragile X syndrome, 2) In the neurocognitive domain, an assessment of frontal lobe functions, social cognition, right hemisphere functions, left hemisphere functions, general intelligence, and academic skills will be done. These evaluations will assess competing hypotheses regarding a specific neurocognitive phenotype in heterozygotes. 3) In the emotional domain, psychopathology, environmental stressors and coping skills will be assessed by a structured interview, direct evaluation and the completion of checklists. These evaluations will also allow us to test several predictions of Laird's imprinting hypothesis, including a lack of involvement of unimprinted heterozygotes (who are fragile X negative or daughters of nonpenetrant males), and the variable influences of X-inactivation on cognitive abilities of imprinted vs. nonimprinted heterozygotes. The study of fragile X-heterozygotes provides a unique opportunity to study the effects of a fairly common X chromosome locus on psychopathology and to advance our understanding of the relationship between neurocognitive problems and emotional dysfunction.